Accumulating data suggest that activation of the innate immune inflammatory response may contribute to the development of major depression. Medically healthy patients with depression exhibit increased plasma concentrations of inflammatory mediators including cytokines of the innate immune system, and administration of innate immune cytokines to animals and humans induces behavioral alterations that overlap with major depression. In addition, cytokines of the innate immune response interact with pathways implicated in the pathophysiology of depression. Increasing interest in targeting the immune system for the treatment of depression has focused on tumor necrosis factor (TNF)-alpha. Plasma concentrations of TNF-alpha have been found to be elevated in patients with major depression, and TNF-alpha is known to activate signaling pathways that alter HPA axis function, monoamine metabolism and synaptic plasticity;all of which are pathophysiologic domains relevant to the development of major depression. Furthermore, laboratory animals with the TNF-alpha receptor gene knocked out exhibit an antidepressant-like phenotype, and the efficacy of traditional antidepressants (i.e. monoamine reuptake inhibitors) has been shown to be related in part to effects on TNF. Finally, antagonism of TNF-alpha activity has been shown to improve depressive symptoms in patients with autoimmune disorders. The long-term goal of the proposed work is to test the cytokine hypothesis of depression using a TNF-alpha antagonist. In the current project, we plan to measure the behavioral response of depressed patients to a single infusion of the TNF-alpha antagonist, infliximab. Given the potential health risks of TNF-alpha antagonism, the proposed study will focus on medically healthy patients with both treatment resistant depression (TRD) and evidence of activation of the innate immune response. TRD is a common and significant public health concern with debilitating consequences in terms of both morbidity and mortality. Interestingly, patients with TRD also appear to be more likely than treatment responsive patients to demonstrate innate immune system activation. We hypothesize that 1) infliximab infusion will decrease depressive symptoms in patients with TRD and increased markers of inflammation and 2) that decreases in depression will correlate with infliximab-induced decreases in TNF-alpha activity and other downstream elements of the innate immune inflammatory response. To test these hypotheses, sixty antidepressant-free subjects with TRD will be randomized in double-blind fashion to a single infusion of infliximab versus saline. Subjects will undergo regular neurobehavioral, immunologic and safety assessments at baseline and at weeks 1, 2, 4, 6 and 8 following infliximab infusion. The proposed translational research will provide novel insights into the role of TNF-alpha in depression and will help define potential biomarkers that predict or monitor success of anti-TNF-alpha therapy.Major depression is the fourth leading cause of overall health burden in the world. Non-response to currently available therapies in up to 30% of depressed patients is a primary contributor to the human and economic cost of the disease. This application proposes to evaluate the novel therapeutic strategy of blocking the cytokine tumor necrosis factor (TNF)-alpha as an intervention for treatment-resistant depression, based on data suggesting that overactive immune system responses, including excessive release of cytokines like TNF- alpha, may contribute to the pathophysiology of the disorder.